Reference Detail

Ref Type Journal Article
PMID (26140595)
Authors Dietlein F, Kalb B, Jokic M, Noll EM, Strong A, Tharun L, Ozretić L, Künstlinger H, Kambartel K, Randerath WJ, Jüngst C, Schmitt A, Torgovnick A, Richters A, Rauh D, Siedek F, Persigehl T, Mauch C, Bartkova J, Bradley A, Sprick MR, Trumpp A, Rad R, Saur D, Bartek J, Wolf J, Büttner R, Thomas RK, Reinhardt HC
Title A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
Journal Cell
Vol 162
Issue 1
Date 2015 Jul 02
URL
Abstract Text KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PF3644022 PF3644022 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PF3644022 PF3644022 is an ATP-competitive MAPK-activated protein kinase-2 (MK2) inhibitor that induces apoptosis in tumor cells (PMID: 26140595).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS G12V Advanced Solid Tumor predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of transformed cells over expressing KRAS G12V in culture, while single agent inhibition had no effect (PMID: 26140595). 26140595
BRAF mutant Advanced Solid Tumor predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of various cancer cell lines harboring BRAF mutations in culture and in cell line xenograft models (PMID: 26140595). 26140595
BRAF mutant colon cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of BRAF mutant colon cancer (PMID: 26140595). 26140595
CDKN2A del lung cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of CDKN2A-deleted lung cancer (PMID: 26140595). 26140595
CDKN2A loss Advanced Solid Tumor predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of multiple cancer cell lines harboring CDKN2A loss and in Cdkn2a-depleted transformed cells in culture (PMID: 26140595). 26140595
KRAS mutant colon cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of KRAS mutant colon cancer (PMID: 26140595). 26140595
KRAS mutant lung adenocarcinoma predicted - sensitive PF-00477736 + PF3644022 Preclinical - Patient cell culture Actionable In a preclinical study, primary tumor cells isolated from lung adenocarcinoma patients harboring KRAS mutations demonstrated increased sensitivity to Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 combination treatment in culture compared to cells lacking KRAS or BRAF mutations (PMID: 26140595). 26140595
KRAS mutant lung cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of KRAS mutant lung cancer (PMID: 26140595). 26140595
KRAS mutant urinary bladder cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of KRAS mutant bladder cancer (PMID: 26140595). 26140595
BRAF N581S lung adenocarcinoma predicted - sensitive PF-00477736 + PF3644022 Preclinical - Patient cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 combination treatment resulted in significant apoptosis in primary tumor cells isolated from a lung adenocarcinoma patient harboring BRAF N581S in culture (PMID: 26140595). 26140595
KRAS mutant pancreatic cancer predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of KRAS mutant pancreatic cancer (PMID: 26140595). 26140595
BRAF V600E Advanced Solid Tumor predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of transformed cells over expressing BRAF V600E in culture, while single agent inhibition had no effect (PMID: 26140595). 26140595
KRAS mutant Advanced Solid Tumor predicted - sensitive PF-00477736 + PF3644022 Preclinical - Cell line xenograft Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of various cancer cell lines harboring KRAS mutations in culture and in cell line xenograft models (PMID: 26140595). 26140595
KRAS mutant pancreatic adenocarcinoma predicted - sensitive PF-00477736 + PF3644022 Preclinical - Patient cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 combination treatment resulted in significant apoptosis in primary tumor cells isolated from pancreas adenocarcinoma patients harboring KRAS mutations in culture (PMID: 26140595). 26140595